What are the recommended first-line therapies and doses for patients with Chronic Kidney Disease (CKD) and hypertension, including Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin II Receptor Blockers (ARBs)?

First-Line Therapies for CKD with Hypertension

ACE inhibitors or ARBs should be initiated as first-line therapy in patients with CKD and hypertension when albuminuria is present, titrated to the highest approved dose tolerated. 1

ACE Inhibitors vs ARBs: Equivalent Efficacy

• Both ACE inhibitors and ARBs are equally effective for renal protection and should be selected based on tolerability rather than efficacy differences 2
• Either class can be used interchangeably as first-line therapy when albuminuria (≥30 mg/g or ≥3 mg/mmol) is present 1
• The choice between these agents should not be based on perceived superiority of one class over the other, as clinical evidence supports equivalent outcomes 2

Specific Dosing Examples

ACE Inhibitors

Lisinopril: 3

• Starting dose: 10 mg once daily for hypertension
• Usual maintenance range: 20-40 mg once daily
• Maximum dose: 80 mg once daily (though doses above 40 mg show minimal additional benefit)
• With concurrent diuretic use: Start at 5 mg once daily

ARBs

Losartan: 4

• Starting dose: 50 mg once daily
• Target dose: 100 mg once daily (72% of patients in RENAAL study received this dose)
• Titration: Increase to 100 mg after one month if blood pressure goal not achieved

Dosing Algorithm

Step 1: Initiate therapy 1

• Start ACE inhibitor or ARB at standard starting dose
• Use lower starting dose (e.g., lisinopril 5 mg) if patient is volume-depleted or on concurrent diuretics 3

Step 2: Titrate to maximum tolerated dose 1, 2

• Critical point: Clinical trials demonstrating renal protection used maximum approved doses 1, 2
• Increase dose every 2-4 weeks as tolerated
• Target the highest approved dose, not just blood pressure control

Step 3: Monitor safety parameters 1

• Check serum creatinine and potassium within 2-4 weeks of initiation or dose increase 1
• Continue therapy if creatinine rises ≤30% within 4 weeks—this reflects hemodynamic changes, not harm 1, 5
• Discontinue only if creatinine rises >30% within 4 weeks 1

When Albuminuria is Present vs Absent

With albuminuria (≥30 mg/g): 1

• ACE inhibitor or ARB is mandatory first-line therapy
• This applies regardless of blood pressure level 1

Without albuminuria: 1

• Dihydropyridine calcium channel blockers (CCBs) or diuretics can be considered as first-line alternatives
• ACE inhibitor/ARB still reasonable but not mandatory

Blood Pressure Targets

• Target BP: <130/80 mmHg in patients with CKD 1
• More intensive target (<120 mmHg systolic) may be considered when tolerated using standardized office BP measurement 5
• Multiple drug classes are typically needed to achieve these targets 1

Additional Agents When Needed

Second-line agents to add (not replace) ACE inhibitor/ARB: 1, 5

• Dihydropyridine CCBs (amlodipine, nifedipine) for additional BP control 5
• Loop diuretics when eGFR <30 mL/min/1.73m² (thiazides become ineffective at this level) 5
• Thiazide or thiazide-like diuretics (chlorthalidone preferred over hydrochlorothiazide) when eGFR ≥30 mL/min/1.73m² 1

Typical multi-drug regimen for CKD Stage 5: 5

• ACE inhibitor or ARB + loop diuretic + dihydropyridine CCB

Critical Pitfalls to Avoid

Never combine ACE inhibitor + ARB + direct renin inhibitor 5, 2

• This triple combination increases adverse events without benefit
• Even dual ACE inhibitor + ARB combination should be avoided due to increased hyperkalemia and acute kidney injury risk 1, 2

Do not underdose these medications 1, 2

• The most common error is using suboptimal doses
• Renal protection in clinical trials was achieved with maximum tolerated doses 1

Do not automatically discontinue for modest creatinine increases 1, 5

• Up to 30% creatinine rise within 4 weeks is acceptable and reflects hemodynamic changes 1
• This does not indicate harm and therapy should continue 5

Do not stop ACE inhibitor/ARB prematurely for hyperkalemia 1

• First attempt to manage hyperkalemia with dietary potassium restriction, volume correction, and review of concurrent medications 1
• Only reduce dose or discontinue if hyperkalemia remains uncontrolled despite these measures 1

Monitoring Protocol

Initial monitoring (within 2-4 weeks of starting or dose change): 1

• Serum creatinine/eGFR
• Serum potassium
• Blood pressure

Ongoing monitoring: 2

• At least annually for creatinine/eGFR and potassium
• More frequently if eGFR <60 mL/min/1.73m² or other risk factors present

Special Considerations

Advanced CKD (eGFR <15 mL/min/1.73m²): 5

• Consider dose reduction or discontinuation only for symptomatic hypotension, uncontrolled hyperkalemia despite treatment, or to reduce uremic symptoms
• Otherwise, continue therapy as cardiovascular benefits may persist 2

Women of childbearing potential: 1

• Advise contraception while on ACE inhibitor or ARB therapy
• Discontinue immediately if pregnancy occurs or is planned 1

Concurrent medications increasing hyperkalemia risk: 2

• NSAIDs, potassium-sparing diuretics, mineralocorticoid receptor antagonists
• Monitor potassium more frequently with these combinations